As a cardiologist, I have been impressed with how frequently young patients are seen with coronary artery disease (CAD) but who lack traditional risk factors, such as elevated levels of low density lipoprotein (LDL). It is now clear that LDL particles are heterogeneous and differ in size, density, chemical composition and immunochemical properties. Work from this laboratory, and other, has demonstrated that such physical heterogeneity results in metabolic heterogeneity as well. Over the next five years I will determine if such heterogeneity is pathophysiologically relevant to the atherogenic process. My investigative work will take place in the productive environment of the La Jolla Atherosclerosis SCOR program, under the direction of my Sponsor, Dr. Josepth L. Witztum. My research will focus on several areas. First, I have documented that alterations in LDL occur in response to bile sequestrant therapy. Such therapy produces LDL particles that are smaller and more dense, consistent with the type of LDL particles found in many normocholesterolemic CAD patients. Since bile sequestrant therapy can produce such particles even in normals, a detailed study of the mechanisms, and the consequences of such changes will be made to determine if this is a model for similar alterations in LDL seen in CAD patients. We have also shown that probucol alters LDL so as to cause an increase in LDL receptor independent uptake of the altered particle. Understanding how probucol enhances clearance of LDL by LDL receptor independent mechanism is also highly relevant to understanding atherogenesis. Another major focus will be to define immunochemical heterogeneity of apo B. I have already defined one genetic polymorphism in apo B by use of a specific mouse monoclonal antibody. In addition I plan to develop new monoclonal antibodies against further allotypes of apo B by use of human-human hybridomas. This technique should facilitate the development of a panel of antibodies to define apo B genetic polymorphism. A detailed study will then be made of subjects with premature CAD to determine if allotypic patterns predict atherosclerosis prone LDL (as has been reported in an animal model). The definition of such apo B polymorphism should also be of considerable importance to those interested in the molecular biology of apo B as well.